There is a plethora of approaches to arranging for controlled release of drugs or growth factors useful in medicine from solid supports. For example, stents that are coated with polymers that contain drugs and release them over time are disclosed in U.S. Pat. No. 7,229,473, representative of a large number of disclosures of such approaches. Devices that release drugs at a controlled rate are described in U.S. Pat. No. 7,647,099. In general, however, the drugs or growth factors used in these approaches are noncovalently contained within the polymeric matrix.
More recently, compositions and methods have been described for controlled release of drugs covalently coupled to macromolecules, such as polyethylene glycol (PEG), in order to enhance pharmaceutical properties, such as half-life, stability, solubility, tolerability, and safety. In one method, drug moieties are coupled to macromolecules through a permanent linker, but this approach is limited by at least two factor: 1) the linker must be attached to the drug moiety at a site that does not hinder biological activity, and 2) permanent conjugates generally cannot cross the cell membrane, so the approach may only be feasible for extracellular drug targets. In a second approach, covalently bound drug-macromolecule conjugates employ PEG as a releasable carrier of the drug or prodrug. Typically, the drug is attached to the carrier by an ester or carbonate linkage that can be cleaved by esterase-catalyzed hydrolysis. Examples are PEG-camptothecin, PEG-SN38, PEG-irinotecan and PEG-docetaxel. Additional adaptations have been made to accommodate amine-containing drugs whereby a PEG moiety is connected by a cleavable ester to a self-immolating carbamate. This technology has been applied to peptides and proteins as well as to daunorubicin, amphotericin, Ara-C and other small molecules. However, drug release rates in these cases is unpredictable and difficult to adjust, because esterase activity varies between species and individuals, and certain compartments are esterase-deficient (e.g., topical, intra-ocular, interstitial areas).
Researches at the Weizmann Institute developed a system in which a protein or polymer carrier is attached to linkers such as fluorenylmethoxycarbonyl (Fmoc) or its 2-sulfo derivative (Fms). These are described in U.S. Pat. No. 7,585,837. These linkers release drugs via a non-enzymatic beta-elimination mechanism; however, tunable control over the release rate remains a problem with this system.
PCT publication WO2009/158668 describes drug-macromolecule conjugates wherein the drug is released through a beta-elimination mechanism, and wherein the rate of beta-elimination is controlled by a trigger independent of the macromolecule itself. This solves a problem left unsolved in the prior art. The release mechanism set forth in the '668 PCT publication has not been applied to instances where a multiplicity of drugs is coupled covalently, but releasably, to the surface of or interstices of solid supports.
The present invention provides for drug-solid support conjugates wherein the drug is released at a controlled rate from the solid support. In addition to providing a controllable rate of release of the drug from the solid support itself, this approach offers a means whereby the coupled drug is protected from hydrolysis by the presence of a protective polymer, such as PEG, on different sites at the surface or interstices of the solid support.